Process for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane

ABSTRACT

The present invention provides a process for producing (Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane, which includes reacting (Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-hydroxymethylcyclopropane with an orthoester and a brønsted acid, and reacting the reaction product with a phthalimidating agent; and a process for producing (Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropane hydrochloride through the above process.

TECHNICAL FIELD

The present invention relates to a novel process for producing

(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropanehydrochloride, which is useful as an antidepresent, and(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropaneas an intermediate thereof.

BACKGROUND ART

(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane(hereafter, may be referred to as the (Z)-phthalimidomethylcyclopropanecompound) is an intermediate of a(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropanehydrochloride (hereafter,(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropane maybe sometimes referred to as the (Z)-aminomethylcyclopropane compound,and (Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropanehydrochloride may be sometimes referred to as the(Z)-aminomethylcyclopropane compound hydrochloride, respectively), whichis useful as an antidepresent. Conventionally, there has been known aprocess for producing the (Z)-phthalimidomethylcyclopropane compound,which comprises chlorinating(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-hydroxymethylcyclopropane(hereafter, may be referred to as the (Z)-hydroxymethylcyclopropanecompound) with thionyl chloride to obtain(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-chloromethylcyclopropane,and reacting the product with a phthalimide salt (see, JP2964041-B).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a process for producingthe (Z)-phthalimidomethylcyclopropane compound and further the(Z)-aminomethylcyclopropane compound hydrochloride at high yield by asimple operation without using a reagent which may generate sulfurdioxide, such as, thionyl chloride, and a low boiling point halogenatedhydrocarbon solvent.

The object and other objects of the present invention will becomeapparent from the following descriptions.

That is, the present invention is as follows.

<1> A process for producing(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropanewhich comprises reacting(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-hydroxymethylcyclopropanewith an orthoester and a brønsted acid, and then reacting the reactionproduct with a phthalimidating agent.<2> The process according to <1>, wherein the reaction product of(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-hydroxymethylcyclopropane,an orthoester and a brønsted acid is an iminium salt of the formula (I)

wherein A⁻ represents conjugated base of a brønsted acid.<3> The process according to <1> or <2 >, wherein the brønsted acid ismethanesulfonic acid.<4> The process according to any of <1> to <3>, wherein the orthoesteris an orthoformic alkyl ester.<5> The process according to <4>, wherein the orthoformic alkyl ester istriethyl orthoformate or trimethyl orthoformate.<6> The process according to any of <1> to <5>, wherein thephthalimidating agent is (1) a phthalimide potassium salt or (2)phthalimide and a base.<7> The process according to <6>, wherein the base is at least oneselected from the group consisting of potassium tert-butoxide, sodiummethoxide, potassium carbonate and triethylamine.<8> The process according to any of <1> to <7>, wherein(Z)-hydroxymethylcyclopropane compound is the compound obtained byreacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane with diethylamine inthe presence of an alkali metal alkoxide.<9> A process for producing (Z)-aminomethylcyclopropane compoundhydrochloride which comprises a step reacting(Z)-hydroxymethylcyclopropane compound with an orthoester and a brønstedacid to obtain reaction product, a step reacting the reaction productwith phthalimidating agent to obtain (Z)-phthalimidomethylcyclopropanecompound, a step reacting (Z)-phthalimidomethylcyclopropane compoundwith aqueous methylamine to obtain (Z)-aminomethylcyclopropane compound,anda step treating (Z)-aminomethylcyclopropane compound with hydrogenchloride.<10> An iminium salt of the formula (I)

wherein A⁻ represents conjugated base of a brønsted acid.<11> The iminium salt according to claim 10, wherein A⁻ is CH₃SO₃ ⁻.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The process for producing the (Z)-phthalimidomethylcyclopropane compoundof the present invention includes the first step wherein the(Z)-hydroxymethylcyclopropane compound is reacted with an orthoester anda brønsted acid to produce an iminium salt (hereafter, may be referredto as the iminium salt (I)) of the formula (I):

wherein A⁻ represents conjugated base of a brønsted acid, and the secondstep wherein the iminium salt (I) is reacted with a phthalimidatingagent.

The first step can be conducted, for example, by mixing the(Z)-hydroxymethylcyclopropane compound, an orthoester and a brønstedacid in a solvent. Although an addition order is not particularlylimited, a method of adding an orthoester to the(Z)-hydroxymethylcyclopropane compound and then adding a brønsted acidis preferable.

The orthoester is not particularly limited and easily available ones canbe used. Examples thereof include orthoformicacid alkyl esters (such astrimethyl orthoformate and triethyl orthoformate), orthoaceticacid alkylesters (such as trimethyl orthoacetate and triethyl orthoacetate),orthobutyricacid alkyl esters (such as trimethyl orthobutyrate andtriethyl orthobutyrate) and orthobenzoicacid alkyl esters (such astrimethyl orthobenzoate and triethyl orthobenzoate), among whichorthoformicacid alkyl esters are preferable, and trimethyl orthoformateand triethyl orthoformate are more preferable.

The amount of the orthoester is preferably from 1 to 10 g equivalentsbased on 1 g equivalent of the (Z) -hydroxymethylcyclopropane compound,and more preferably from 1.2 to 2 g equivalents, in view of preventionof generation of material residues or by-products, and reactionefficiency.

The brønsted acid is not particularly limited and easily available onescan be used. Examples thereof include methanesulfonic acid,toluenesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid andhydrogen chloride, among which methanesulfonic acid is preferable inview of reactivity.

The amount of the brønsted acid is preferably from 1 to 10 g equivalentsbased on 1 g equivalent of the (Z)-hydroxymethylcyclopropane compound,and more preferably from 1 to 1.5 g equivalents, in view of completionof the reaction or reaction efficiency.

The first step can generally be conducted in a solvent, and anorthoester can also serve as the solvent. The solvent is not limited aslong as it does not inhibit the reaction, and hydrocarbon solvents suchas toluene and aprotic polar solvents such as N,N-dimethylformamide canbe used alone or in combination. The amount of the solvent is preferably5 parts by weight or less based on 1 part by weight of the(Z)-hydroxymethylcyclopropane compound.

The reaction temperature of the first step is generally from 0 to 100°C., and preferably from 20 to 40° C. The reaction time is generally from1 to 24 hours, and preferably from 1 to 10 hours.

In the reaction mixture after completion of the first step, the iminiumsalt (I), its counter ion is conjugated base of the used brønsted acid,is contained. The reaction mixture, as it is, can be used for the secondstep. The first step and the second step can be conducted in the samereaction vessel, so called in one-pot. In such a case, before the secondstep, the reaction mixture after completion of the first step can beconcentrated and substituted by another solvent.

Also, the iminium salt (I) can be isolated by removing the solvent underreduced pressure, and may be optionally purified by conventional meanssuch as decantation with an organic solvent or chromatography.

The iminium salt (I) produced in the first step is a novel compound, anda useful synthetic intermediate of the (Z)-aminomethylcyclopropanecompound hydrochloride as an antidepresent. A⁻ in the iminium salt (I)is preferably CH₃SO₃ ⁻.

The second step can be conducted, for example, by mixing the reactionmixture after completion of the first step or the isolated iminium salt(I) with a phthalimidating agent in a solvent. Although an additionorder is not particularly limited, a method of adding dropwise thereaction mixture after completion of the first step to thephthalimidating agent is preferable.

As the phthalimidating agent, a phthalimide salt is used. Examplesthereof include phthalimide potassium salt, phthalimide sodium salt andphthalimide triethylamine salt, among which phthalimide potassium saltis preferred. The amount of the phthalimidating agent is preferably from1 to 10 g equivalents based on 1 g equivalent of the (Z)-hydroxymethylcyclopropane compound (1 g equivalent of the iminium salt(I), assuming that the yield of the iminium salt (I) in the first stepis 100%) that is used in the first step, and more preferably from 1 to 2g equivalents, in view of completion of the reaction or reactionefficiency.

The phthalimide salt may be produced from phthalimide and a base in areaction system. In this case, examples of the base include

at least one kind of potassium tert-butoxide, sodium methoxide,potassium carbonate, triethylamine and the like. The amount of the baseis preferably from 1 to 10 g equivalents, and more preferably from 1 to2 g equivalents, based on 1 g equivalent of phthalimide.

The second step is preferably conducted in a solvent. Examples of thesolvent include single solvents and mixed solvents such as aprotic polarorganic solvents (such as N,N-dimethylformamide, N,N-dimethylacetoamide,N,N′-dimethylimidazolidinone and N-methyl pyrrolidone) andproticorganicsolvents (such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol andpropylene glycol), among which aprotic polar organic solvents arepreferred in view of reactivity, and N,N-dimethylformamide andN,N-dimethylacetoamide are particularly preferred. The amount of thesolvent is preferably from 1 to 50 parts by weight based on 1 part byweight of the (Z)-hydroxymethylcyclopropane compound that is used in thefirst step.

The reaction temperature of the second step is generally from 0 to 150°C., and preferably from 20 to 80° C. The reaction time is generally from1 to 20 hours, and preferably from 1 to 5 hours.

After completion of the second step, the (Z)-phthalimidomethylcyclopropane compound can be isolated and purified bya conventional method. For example, isolation can be conducted by addingwater or the like to the reaction mixture, filtering and washing theprecipitated crystal, or extracting the reaction mixture with an organicsolvent, followed by washing with water, and concentration. Furthermore,purification may be conducted by crystallization or chromatography.

The (Z)-aminomethylcyclopropane compound hydrochloride, which is usefulas an antidepresent, can be derived from the(Z)-phthalimidomethylcyclopropane compound obtained by the presentinvention by a known method. For example, as described in JapaneseExamined Patent Publication No. 5-67136, the (Z)-aminomethylcyclopropanecompound hydrochloride can be derived by reacting the(Z)-phthalimidomethylcyclopropane compound with an aqueous methylaminesolution to obtain the (Z)-aminomethylcyclopropane compound, andtreating the compound with hydrogen chloride. The(Z)-hydroxymethylcyclopropane compound is a known compound, and asdescribed in JPH02-262558-A, for example, the compound can be producedby reacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane (see Synthesis,1978, 304-305) with diethylamine in the presence of a Lewis acid aminecomplex. However, since a low boiling point halogenated hydrocarbon suchas dichloroethane is required in this method, there arises anenvironmental problem similarly to the above described conventionalprocess for producing the (Z)-phthalimidomethylcyclopropane compound.

Accordingly, a method of reacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane with diethylamine in the presence of an alkali metal alkoxide,which is proposed by the present inventors, is preferable.

The method can be conducted, for example, by mixing2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane, diethylamine and an alkalimetal alkoxide in a solvent.

The amount of diethylamine is generally from 1 to 10 g equivalents, andpreferably from 2 to 4 g equivalents, based on 1 g equivalent of2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane.

Examples of the alkali metal alkoxide include alkali metal salts of analcohol having 1 to 4 carbon atoms, such as lithium methoxide, sodiummethoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,potassium ethoxide, sodium t-butoxide and potassium t-butoxide. Sodiummethoxide or potassium methoxide is preferred, and sodium methoxide isparticularly preferred.

The amount of the alkali metal alkoxide is generally from 1 to 5 gequivalents, and preferably from 1.5 to 4 g equivalents, based on 1 gequivalent of 2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane.

The form of the alkali metal alkoxide is not particularly limited, andit may be in the form of solid or solution. When a solution is used, asolution of the alcohol solvent corresponding to an alkali metalalkoxide to be used (for example, sodium methoxide in methanol) ispreferably selected. The alcohol solvent is contained as a portion of areaction solvent.

The kind of the solvent to be used is not limited as long as it does notinhibit the reaction, and examples thereof include methanol, ethanol,toluene, hexane, heptane and the like. These solvents can be used aloneor in combination.

The amount of the solvent is generally from 1 to 10 ml, and preferablyfrom 3 to 5 ml, based on 1 g of 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane.

The reaction temperature is generally from 0 to 100° C., preferably from20 to 80° C., and particularly preferably from 20 to 30° C., and thereaction time is generally from 3 to 30 hours, although it variesdepending on the reaction amount, the reaction temperature or the like.

After completion of the reaction, the (Z)-hydroxymethylcyclopropanecompound can be obtained by any of known isolation or purificationmethods in the field or in combination thereof, such as extraction witha solvent, silica gel column chromatography, high performance liquidchromatography, distillation under reduced pressure andrecrystallization.

Hereinafter, the present invention will be described in more detail byway of examples, but the present invention is not limited thereto.

Preparation Example 1

(Z)-1-phenyl-1-(N, N-diethylaminocarbonyl)-2-hydroxymethylcyclopropane

Diethylamine (250.4 g, 3.42 mol) was added to a mixture solution of2-oxo-1-phenyl-3-oxabicyclo[3.1.0] hexane (198.8 g, 1.14 mol) andtoluene (198.8 g), and a 28% sodium methoxide/methanol solution (660.4g, 3.42 mol) was added dropwise at 20 to 30° C., followed by stirringfor 8 hours. The reaction solution after stirring was added dropwise toa mixture solution of water (554.8 g) and toluene (596.4 ml), and thenacetic acid (226.0 g) was added dropwise, followed by separation of thesolution. The obtained aqueous layer was extracted again with toluene(397.6 ml) . The organic layers were combined, washed with water, andconcentrated under reduced pressure to obtain the title compound as a50% toluene solution.

(It was confirmed by HPLC analysis (HPLC: LC-10Avp, ODS column 4.6mm×150 mm, manufactured by Shimadzu Co.) that the title compound wascontained in an amount of 265.3 g. The yield was 93.8%.)

Example 1

(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane

Ethyl orthoformate (14.4 g, 0.097 mol) was added to a toluene solution(40.0 g) containing(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-hydroxymethylcyclopropane(20.0 g, 0.081 mol) in a reaction vessel, and then methanesulfonic acid(9.5 g, 0.089 mol) was added dropwise at 15 to 35° C. over one hour.After the instillation, the solution was stirred for 1.5 hours, heatedto 40° C., and concentrated under reduced pressure.N,N-dimethylformamide (20 ml) was added, followed by concentration underthe same conditions to obtain a concentrated solution (47.1 g).

Separately, phthalimide potassium salt (18.7 g, 0.101 mol) and 92 ml ofN,N-dimethylformamide were charged in a reaction vessel, and theafore-mentioned concentrated solution was added dropwise to the obtainedsolution at 40° C. over 2 hours, followed by stirring for one hour.

The reaction solution was cooled to about 20° C., and water (67.5 ml)was added dropwise to the cooled reaction solution over 3 hours. Themixture was filtered, washed with water (67.5 ml), and dried at about60° C. under reduced pressure to obtain the title compound (28.8 g) as awhite crystal. The yield was 93.2% and the purity was 98.6%.

Physical data: ¹H—NMR (CD₃OD, 400 MHz) δ: 0.62 (3H, t, J=7.0 Hz), 1.11(1H, dd, J=5.2, 8.8 Hz), 1.17 (3H, t, J=7.0 Hz), 1.63 (1H, dd, J=5.2,6.0 Hz), 2.25 (1H, m), 3.18 (1H, m), 3.30-3.43 (3H, m), 3.67 (1H, m),4.07 (1H, dd, J=5.0, 14.2 Hz), 7.21-7.34 (5H, m), 7.80-7.89 (4H, m).

Example 2

(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropanehydrochloride

Water (35.0 kg) and toluene (79.0 kg) were added to(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane(18.2 kg, 48.4 mol), and a 40 wt % aqueous solution of monomethylamine(37.7 kg, 485 mol) was added dropwise to the mixture, followed bystirring at 20° C. for 20 hours. After separation of the reactionmixture, the aqueous layer was extracted twice with toluene. The organiclayers were combined, dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure. Ethyl acetate (67.1 kg) andisopropyl alcohol (9.0 kg) were added to the concentrated residue, and4N hydrogen chloride-ethyl acetate (12.5 kg, 55.9 mol) was addeddropwise to a solution thereof. The resulting crystal was filtered,washed with ethyl acetate and dried to obtain(Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-aminomethylcyclopropanehydrochloride (11.9 kg) as a white powder. The yield was 86.9%.

Physical data: ¹H—NMR (D₂O, 400 MHz) δ: 0.87 (3H, t, J=7.0 Hz), 1.08(3H, t, J=7.0 Hz), 1.72-1.84 (3H, m), 2.43 (1H, m), 3.25-3.44 (4H, m),3.71 (1H, m), 7.13-7.28 (5H, m), 8.80 (3H, br-s).

Example 3

N,N-diethyl-(1-phenyl-3-oxabicyclo[3.1.0]hex-2-ylidene) iminiummethanesulfonate

A concentrated solution before conducting phthalimidation was producedin the same manner as in Example 1, and some of the concentratedsolution was taken and evaporated to dryness under reduced pressure.After adding n-heptane to the residue, a decantation operation wasrepeated several times, followed by evaporation to dryness under reducedpressure to obtain the title compound as a water-soluble pale yellow oil(purity: 98.6%).

Physical data: ¹H—NMR (D₂O, 400 MHz) δ: 0.26 (3H, t, J=7.2 Hz), 0.71(3H, t, J=7.2 Hz), 1.14 (1H, m), 1.90 (1H, m), 2.18 (1H, m), 2.24 (3H,s), 2.75 (1H, m), 2.95 (1H, m), 3.13 (2H, m), 4.30 (1H, d, J=9.6 Hz),4.57 (1H, dd, J=4.8, 9.6 Hz), 6.93-7.00 (5H, m). LC-MS (ESI, transferphase: acetonitrile 0.1% aq. CF₃CO₂H) M⁺¹: 344 (detected bytrifluoroaceticacid salt)

CI-MS: M⁺¹ 326

According to the present invention, in the case of producing the(Z)-phthalimidomethylcyclopropane compound, a chlorination agent, whichgenerates sulfur dioxide during the reaction, is not required because achloro compound or an acid chloride is not by way of the reaction,unlike a conventional method. Furthermore, it is not required to use alow boiling point halogenated hydrocarbon solvent such asdichloroethane, which may cause an environmental problem.

Also, as compared to the case where a chlorination agent is used,coloration of the product can be suppressed and thus the process of thepresent invention is excellent as a process for producing anintermediate of drugs.

Furthermore, since a first step and a second step are conducted in thesame reaction vessel, one step can substantially be omitted, and thusthe process of the present invention is also excellent in economy.

1. An iminium salt of the formula (I)

wherein A⁻ represents conjugated base of a brønsted acid.
 2. The iminiumsalt according to claim 1, wherein A- is CH3SO3-.